Process for preparing azacycloalkanoylaminothiazoles (LD 137e)

ABSTRACT

The present invention relates to new, efficient processes for the preparation of 5-(-2-oxyazolylalkylthio)-2-azacycloalkanoylaminothiazole compounds of formula I  
                 
 
     or a pharmaceutically acceptable salt thereof, wherein:  
     R is alkyl, aryl or heteroaryl;  
     R 1 , R 2 , R 3 , R 4  and R 5  are each independently hydrogen, alkyl, aryl or heteroaryl;  
     R 6  and R 7  are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;  
     R 8  is hydrogen, alkyl, aryl, heteroaryl, CONR 9 , R 10 , COR 11  or COOR 12 ;  
     R 9 , R 10 , R 11  and R 12  are each independently hydrogen, alkyl or aryl;  
     m equals 0 to 5; and  
     n equals 0 to 5,  
     which are novel, potent inhibitors of cyclin dependent kinases (cdks). The present invention further concerns new key intermediate compounds, a quaternary ammonium salt of formula III′ and a 2-oxazolylalkyl derivative of formula IX.

CROSS-REFERENCE TO RELATED U.S. APPLICATIONS

[0001] This application is a continuation-in-part of (1) patentapplication Ser. No. 09/616,627, filed on Jul. 26, 2000 and (2) patentapplication Ser. No. 09/616,629, filed on Jul. 26, 2000, which arecontinuation-in-part applications of patent application No. Ser.09/464,511, filed Dec. 15, 1999.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] Not Applicable

REFERENCE TO A “Microfiche Appendix”

[0003] Not Applicable

BACKGROUND OF THE INVENTION

[0004] 1. Field of the Invention

[0005] The present invention concerns new processes for the preparationof 5-(2-oxazolyalkylthio-2-azacycloalkanoylaminothiazoles and analogs,inhibitors of cyclin dependent kinases.

[0006] 2. Description of the Related Art

[0007] The 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazolecompounds of formula I

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] R is alkyl, aryl or heteroaryl;

[0010] R¹, R², R³, R⁴ and R⁵ are each independently hydrogen, alkyl,aryl or heteroaryl;

[0011] R⁶ and R⁷ are each independently hydrogen, alkyl, aryl,heteroaryl, halogen, hydroxy or alkoxy;

[0012] R⁸ is hydrogen, alkyl, aryl, heteroaryl, CONR⁹R¹⁰, COR¹¹ orCOOR¹²;

[0013] R⁹, R¹⁰, R¹¹ and R¹² are each independently hydrogen, alkyl oraryl;

[0014] m equals 0 to 5; and

[0015] n equals 0 to 5,

[0016] are novel, potent inhibitors of cyclin dependent kinases (cdks).They are useful in the therapy of proliferative diseases, for example,cancer, inflammation, autoimmune diseases such as arthritis, viraldiseases, fungal diseases, chemotherapy-induced alopecia,neurodegenerative disorders such as Alzheimer's disease andcardiovascular disease. More specifically, the compounds of formula Iare useful in the treatment of a variety of cancers such as bladder,breast, colon, kidney, liver and lung cancers.

[0017] WO 9924416 and corresponding U.S. Pat. No. 6,040,321 describe thepreparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles, keyintermediates in the synthesis of5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles of formula I,by reacting 5-acetylthio-2-acetylaminothiazole with a base followed bytrapping the thiolate with a 2-oxazolylalkyl halide. Hydrolysis of theresulting 5-(2-oxazolylalkylthio)-2-acetylaminothiazole compoundsafforded the 5-(2-oxazolylalkylthio)-2-aminothiazole key intermediates.The requisite 2-oxazolylalkyl halides were prepared by (i) reaction ofβ-hydroxy amines with α-chloroacyl chlorides followed by oxidation ofthe resulting β-hydroxy-α-chloramides and subsequent oxazole ringformation (K. S. Kim et al., WO 9924416, May 20, 1999) or (ii) reactionof α-diazo ketones with α-chloronitriles (K. S. Kim et al., WO 9924416,May 20, 1999; T. Ibata et al., Bull. Chem. Soc. Japan 1979, 52, 3597).Although a variety of 5-(2-oxazolylalkylthio)-2-aminothiazoles can beprepared by this method, this process is not amenable to large scalesynthesis due to the commercial availability of the starting5-acetylthio-2-acetylaminothiazole, the use of hazardous α-diazo ketonesand expensive chromatographic separation of products.

[0018] Reaction of α-halo ketones with azide to give α-azido ketones hasbeen previously reported in the literature (A. Hassner et al., AngewChem. Int. Ed. Engl. 1986, 25, 478; M. G. Nair et al., J. Med. Chem.1980, 23, 899; H. -J. Ha et al., Synth. Commun. 1994, 24, 2557).Reaction of α-sulfonyloxy ketones with azide to give α-azido ketones hasalso been previously reported (T. Patonay et al., J. Org. Chem. 1994,59, 2902; G. A. Revelli et al., Synth. Commun. 1993, 23, 1111).

[0019] Reduction of α-azido ketones to α-amino ketones has beendescribed in the literature (H. -J. Ha et al., Synth. Commun. 1994, 24,2557; J. P. Sanchez et al., J. Heterocycl. Chem. 1988, 25, 469; S. K.Boyer et al., J. Org. Chem. 1985, 50, 3408). Reaction of α-amino ketoneswith α-halo acyl halides to give the corresponding amides has furtherbeen described (G. T. Newbold et al., J. Chem. Soc. 1948, 1855; G. T.Newbold et al., J. Chem. Soc. 1950, 909).

[0020] Reaction of alkylthiouronium salts with alkyl halides to givesulfides has been previously reported (H. Chen et al., Synth. Commun.1990, 20, 3313). Reaction of alkylthiols with 5-bromo-2-aminothiazole togive 5-alkylthio-2-aminothiazoles has been reported (J. B. Dickey etal., J. Org. Chem. 1959, 24, 187).

BRIEF SUMMARY OF THE INVENTION

[0021] This invention concerns new efficient processes for thepreparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles. The processesinvolve new strategies for the preparation of 2-oxazolylalkyl halidesand 5-(2-oxazolylalkylthio)-2-aminothiazoles which include the method ofmaking new key intermediate quaternary ammonium salts and2-oxazolylalkyl sulfide derivatives. This invention further relates toprocesses for the preparation of5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs,inhibitors of cyclin dependent kinases.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Not Applicable

DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention relates to new, more efficient processesfor the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles withapplication to the synthesis of5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs,inhibitors of cyclin dependent kinases. The process generally involvesreaction of α-halo ketones II with an azide to give α-azido ketones imp.Reduction of Imp with a reducing reagent gives α-amino ketones IV. Froma practical standpoint, safety concerns make this reaction through theazide economically unfeasible.

[0024] Alternatively and more advantageously, the α-amino ketones TV areprepared by reaction of α-halo ketones II with a cyclicalkylenetetramine such as hexamethylenetetramine and the like, followedby hydrolysis of the resulting, new quaternary ammonium salt III′. Thisreaction provides excellent yields of the desired intermediate compoundIV, above 90%, yet in a safer manner.

[0025] Thereafter, reacting the α-amino ketones IV with an α-halo acylhalide V in the presence of a base or, alternatively, coupling theα-amino ketones IV with an α-halo acid, produces the correspondingamides VI. Then, ring closure of VI with a dehydrating reagent affords2-oxazolylalkyl halides VII. When a conventional dehydrating reagentsuch as trihalophosphorus oxide like POCl₃ is used, product isolation isdifficult due to the formation of large amounts of hydrochloric andphosphoric acids. Thus, the process of the present invention preferablyutilizes the Burgess' reagent which produces excellent yields andpermits easy, safe product isolation from water.

[0026] Subsequent treatment of 2-oxazolylalkyl halides VII withsulfur-containing reagent VII or VIII′ affords new key intermediatecompounds, 2-oxazolylalkyl sulfides IX. Coupling of IX with5-halo-2-aminothiazole X gives 5-(2-oxazolylalkylthio)-2-aminothiazolesXI. Coupling of XI with an azacycloalkanoic acid derivative XII affordsthiazolyl amides XIII, which may be deprotected (in the case where P isa protecting group, e.g., Boc) to give5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles I, where R⁷ ishydrogen, inhibitors of cyclin dependent kinases.

[0027] The above-described reactions are illustrated in the below Scheme1.

[0028] In formulas I-XIII of Scheme 1, the following terms apply:

[0029] R is alkyl, aryl or heteroaryl;

[0030] R¹, R², R³, R⁴ and R⁵ are each independently hydrogen, alkyl,aryl or heteroaryl;

[0031] R⁶ and R⁷ are each independently hydrogen, alkyl, aryl,heteroaryl, halogen, hydroxy or alkoxy;

[0032] R⁸ is hydrogen, alkyl, aryl, heteroaryl, CONR⁹R¹⁰, COR¹¹ orCOOR¹²;

[0033] R⁹, R¹⁰, R¹¹ and R¹² are each independently hydrogen, alkyl oraryl;

[0034] L is halogen or sulfonate (RSO₂O—, CF₃SO₂O—, etc.);

[0035] M is hydrogen, Li, Na, K, Cs or quaternary ammonium (R₄N);

[0036] X is hydroxy, halogen or acyloxy (RCOO—, ROCOO—, etc.);

[0037] Y is O, S, NH, N-alkyl, N-aryl or N-acyl;

[0038] Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl,NH₂, N-alkyl, N-aryl or N-acyl;

[0039] P is a nitrogen-protecting group (Boc, Cbz, R₃Si, etc.);

[0040] m equals 0 to 5; and

[0041] n equals 0 to 5.

[0042] Listed below are definitions of various terms used to describethe compounds involved in the processes of the present invention. Thesedefinitions apply to the terms as they are used throughout thespecification (unless specifically indicated otherwise) eitherindividually or as part of a larger group. It should be noted that anyheteroatom with unsatisfied valences is assumed to have the hydrogenatom to satisfy the valences.

[0043] The term “alkyl” or “alk” (i.e., derivative forms of alkyl)refers to optionally substituted straight chain, branched or cyclicmonovalent alkane (saturated hydrocarbon) derived radicals containingfrom 1 to 12 carbon atoms. When substituted, alkyl groups may besubstituted with up to four substituent groups at any available point ofattachment. Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and thelike. The alkyl can be optionally substituted with one or more halogensor alkyl groups such as, for example, trifluoromethyl,4,4-dimethylpentyl, 2,2,4-trimethylpentyl, etc.

[0044] The term “aryl” or derivative forms thereof refers to monocyclicor bicyclic aromatic rings, e.g., phenyl, substituted phenyl and thelike, as well as groups which are fused, e.g., napthyl, phenanthrenyland the like, containing from 6 to 30 carbon atoms. An aryl group canthus contain at least one ring having 6 atoms, with up to five suchrings being present, containing up to 22 or 30 atoms therein, dependingupon optionally alternating (resonating) double bonds between carbonatoms or suitable heteroatoms. Examples of aryl groups include, but arenot limited to, phenyl, naphthyl, anthryl, biphenyl and the like.

[0045] The term “acyl” refers to the radical RCO—, taken alone or incombination, for example, with oxygen, nitrogen, sulfur, etc. The term“halogen” or “halo” refers to chlorine, bromine, fluorine or iodine,with bromine being the preferred halogen.

[0046] The term “heteroaryl” refers to a monocyclic aromatic hydrocarbongroup having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to10 atoms, containing at least one heteroatom, O, S or N, in which acarbon or nitrogen atom is the point of attachment, and in which one ortwo additional carbon atoms is optionally replaced by a heteroatomselected from O or S, and in which from 1 to 3 additional carbon atomsare optionally replaced by nitrogen heteroatoms, said heteroaryl groupbeing optionally substituted as described herein. Exemplary heteroarylgroups include, but are not limited to, thienyl, furyl, pyrrolyl,pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl,triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl,pyrimidinal, triazinylazepinyl, indolyl, isoindolyl, quinolinyl,isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl,benzoxadiazolyl, benzofurazanyl, etc. The heteroaryl groups can beoptionally substituted by one or more groups which include, but are notlimited to, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl,alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, amino,alkylS(O)_(m) (where m=0, 1 or 2), thiol and the like.

[0047] When a functional group is termed “protected,” this means thatthe group is in modified form to preclude undesired side reactions atthe protected site. Suitable protecting groups for the compoundsinvolved in the present processes will be recognized from thespecification taking into account the level of skill in the art, andwith reference to standard textbooks such as T. W. Greene et al.,Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).

[0048] The term “pharmaceutically acceptable salt” refers to those saltsof the biologically active compounds which do not significantly oradversely affect the pharmaceutical properties of the compounds such as,for example, toxicity, efficacy, etc. and include those salts which areconventionally employed in the pharmaceutical industry. Suitableexamples of salts include, but are not limited to, those formed withinorganic or organic acids such as hydrochloride, hydrobromide, sulfate,phosphate, etc. Also included, particularly for the intermediatecompounds of the invention, are salts which are unsuitable forpharmaceutical utility but which can be employed otherwise, for example,for isolation or purification of free active compounds or theirpharmaceutically acceptable salts.

[0049] All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The definition of the compounds employed in the processes of theinvention embraces all possible stereoisomers and their mixtures. Thedefinition further embraces the racemic forms and the isolated opticalisomers having the specified activity. The racemic forms can be resolvedby physical methods such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives orseparation by chiral column chromatography. The individual opticalisomers can be obtained from the racemates by conventional methods suchas, for example, salt formation with an optically active acid followedby crystallization.

[0050] It should be understood that solvates (e.g., hydrates) of thecompounds of formula I and the intermediate compounds are also withinthe scope of the present invention. Methods of solvation are generallyknown in the art. Therefore, the compounds useful in the processes ofthis invention may be in the free or hydrate form.

[0051] As set forth in Scheme 1, the processes for the preparation of5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogsinvolve the following transformations:

[0052] (a) reacting an α-substituted ketone II such as, for example, anα-halo ketone, with an azide in a suitable solvent or solvent mixturesto give an α-azido ketone III; or, more desirably, (a′) reacting anα-substituted ketone II like the α-halo ketone with a cyclicalkylenetetramine such as, for example, hexamethylenetetramine in asuitable solvent or solvent mixtures to give a new quaternary ammoniumsalt III′.

[0053] The α-halo ketone includes α-halo aliphatic and α-halo aromaticketones. The preferred α-halo ketones are α-halo pinacolones withα-bromo pinacolone most preferred. A sulfonate, for example, RSO₂O—(where R is alkyl, aryl or heteroaryl), CF₃SO₂O— and the like, may besubstituted for the halogen in the α-position. The azides include bothmetal azides and quaternary ammonium azides. The metal azides arepreferred with sodium azide most preferred. Suitable solvent(s) includesolvents such as hydrocarbons, ethers, amides, for example,dimethylformamide, ketones, etc., or mixtures thereof, with ketones suchas acetone preferred for both reactions (a) and (a′).

[0054] (b) reacting the α-azido ketone III obtained in step (a) with areducing reagent in a suitable solvent or solvent mixtures to give anα-amino ketone IV, or, more desirably, (b=40 ) reacting the quaternaryammonium salt III′ obtained in step (a′) with an acid in a suitablesolvent or solvent mixtures to give an α-amino ketone IV.

[0055] The reducing reagent in reaction (b) includes hydrogen in thepresence of a transition metal catalyst such as palladium, trialkyl ortriarylphosphines like triphenylphosphine. Hydrogen in the presence of atransition metal catalyst is preferred with hydrogen and palladium overactivated carbon most preferred. Suitable solvent(s) in reaction (b)include solvents such as hydrocarbons, ethers, alcohols and the like, ormixtures thereof, with alcohol such as methanol preferred.Alternatively, the reduction reaction can be carried out in the presenceof an acidic medium such as, for example, hydrochloric acid in ethanolto give α-amino ketone acid salt which can be isolated as the acid saltor free amine forms.

[0056] The acid in reaction (b′) includes, but is not limited to, proticacids such as HCl, HBr, HI, H₂SO₄, H₃PO₄, etc., with HCl preferred.Suitable solvent(s) in reaction (b′) include solvents such ashydrocarbons, ethers, alcohols and the like, or mixtures thereof, withalcohol such as ethanol preferred. The α-amino ketone product may beisolated as the salt or free base forms.

[0057] (c) reacting (acylating) the α-amino ketone IV or its acid saltobtained in step (b) or (b′) with an α-substituted acyl derivative Vsuch as, for example, an α-halo acyl halide, in the presence of a baseand in a suitable solvent or solvent mixtures to give an amide VI.

[0058] The α-halo acyl halide V includes α-alkyl or aryl substituted orunsubstituted α-halo acyl halide with the latter preferred. The mostpreferred α-halo acyl halide is α-chloroacetyl chloride. The base usedin the reaction includes, but is not limited to, aromatic and aliphaticorganic amines with the latter preferred. The most preferred base istriethylamine. Suitable solvent(s) include aprotic solvents such ashydrocarbons, halogenated hydrocarbons, ethers, esters and the like, ormixtures thereof, with halogenated hydrocarbons such as dichloromethanepreferred. Alternatively, the reaction can be carried out using anα-substituted acid instead of the α-substituted acyl derivative and thenemploying a coupling reagent such as a water-soluble diimide likecarbodiimide, haloformate, thionyl halide, etc. In either reaction, asulfonate, for example, RSO₂O— (where R is an alkyl, aryl orheteroaryl), CF₃SO₂O— and the like, may be substituted for the halogenin the α-position of the α-halo acyl halide or the α-halo acid reactantswhich are illustrated.

[0059] (d) reacting the amide VI obtained in step (c) with a dehydratingreagent in a suitable solvent or solvent mixtures to give the cyclized2-oxazolylalkyl derivative VII such as, for example, the 2-oxazolylalkylhalide.

[0060] Advantageously, the reaction is carried out using(methoxycarbonylsulfamoyl)-triethylammonium hydroxide (Burgess' reagent)as the dehydrating reagent. Suitable solvent(s) include hydrocarbons,halogenated hydrocarbons, ethers and the like, or mixtures thereof. Mostpreferred is the use of the Burgess' reagent in tetrahydrofuran.Suitable dehydrating reagents also include, but are not limited to,other bases, acids, acid anhydrides and the like, such as, e.g.,concentrated sulfuric acid, polyphosphoric acid, etc. Although lessconveniently, the dehydrating reagent, for instance, can betrihalophosphorus oxide such as tribromophosphorus oxide ortrichlorophosphorus oxide, alone or with a solvent like toluene.

[0061] (e) reacting the 2-oxazolylalkyl derivative VII obtained in step(d) with a sulfur-containing reagent VIII or VIII′ in a suitable solventor solvent mixtures to give 2-oxazolylalkyl sulfide IX, a new keyintermediate compound.

[0062] The sulfur-containing reagent includes N-substituted orunsubstituted thioureas, thio acids or salts such as thioacetic acid orits salt, xanthic acids or salts such as ethylxanthic acid potassiumsalt. Unsubstituted thiourea is preferred. Suitable solvent(s) includehydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcoholsand the like, or mixtures thereof, with alcohol such as methanol orethanol preferred.

[0063] (f) reacting the 2-oxazolylalkyl sulfide IX obtained in step (e)with a 5-halo-2-aminothiazole X in the presence of a base and in asuitable solvent or solvent mixtures to give5-(2-oxazolylalkylthio)-2-aminothiazole XI.

[0064] The 5-halo-2-aminothiazole includes 4,N-substituted orunsubstituted 5-halo-2-aminothiazoles with 5-bromo-2-aminothiazolepreferred. A suitable base includes, but is not limited to, metalhydroxide, metal alkoxides, metal carbonates and aqueous amines such asammonium hydroxide. Sodium hydroxide is preferred. Suitable solvent(s)include solvents such as hydrocarbons, halogenated hydrocarbons, ethers,esters, amides, alcohols and the like, or mixtures thereof, withhalogenated hydrocarbons such as dichloromethane preferred.

[0065] (g) reacting the 5-(2-oxazolylalkylthio)-2-aminothiazole XIobtained in step (f) with an azacycloalkanoic acid derivative XII in thepresence of a coupling reagent in a suitable solvent or solvent mixturesto give thiazolyl amide XIII.

[0066] The azacycloalkanoic acid derivative includes N-protectedderivatives, for example, N-protected isonipecotic acid or N-protectednipecotic acid. The preferred nitrogen-protecting groups are Boc, Cbz,silicon derivatives and the like with Boc being the most preferred. Thecoupling reagent includes, but is not limited to, water-solublecarbodiimides, haloformates and the like, with carbodiimides such asalkylcarbodiimides being preferred. Suitable solvent(s) include solventssuch as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides,etc., or mixtures thereof, with halogenated hydrocarbons such asdichloromethane preferred.

[0067] (h) reacting the thiazolyl amide XIII obtained in step (g) with adeprotecting reagent in a suitable solvent or solvent mixtures to give adesired 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole I (whereR⁷ is hydrogen).

[0068] The choice of the deprotecting reagent is based on the nature ofthe protecting group (P). For the Boc protecting group, the preferreddeprotecting reagent is an acid such as hydrochloric acid ortrifluoroacetic acid and suitable solvent(s) for such deprotectingreaction include solvents such as hydrocarbons, halogenatedhydrocarbons, ethers, esters, amides and the like, or mixtures thereof,with halogenated hydrocarbons such as dichloromethane preferred.

[0069] The starting compounds of Scheme 1 are commercially available ormay be prepared by methods known to one of ordinary skill in the art.

[0070] To further illustrate Scheme 1, a process to make5-(5-t-butyl-2-oxazolylmethylthio)-2-azacycloalkanoylaminothiazoles andanalogs thereof, for example, starts with reaction of α-bromo pinacoloneII (R=Bu-t, R¹═H, L=Br) with sodium azide to give an α-azido pinacoloneIII (R=Bu-t, R¹═H). Reduction of α-azido pinacolone III (R=Bu-t, R¹═H)with a reducing reagent gives α-amino pinacolone IV (R=Bu-t, R¹═H).Alternatively and more desirably, the α-amino pinacolone IV (R=Bu-t,R¹═H) is prepared by reaction of α-bromo pinacolone II (R=Bu-t, R¹═H,L=Br) with hexamethylenetetramine followed by hydrolysis of theresulting quaternary ammonium salt III′ (R=Bu-t, R¹═H, L=Br). Couplingof α-amino pinacolone IV (R=Bu-t, R¹═H) with an α-chloroacetyl chlorideV (R²═R³═H, L=X═Cl) produces amide VI (R=Bu-t, R¹═R²═R³═H, L=Cl). Ringclosure of VI with a dehydrating reagent affords5-t-butyl-2-oxazolylmethyl chloride VII (R=Bu-t, R¹═R²═R³═H, L=Cl).Treatment of VII with sulfur-containing reagent VIII or VIII′ such asthiourea affords 5-t-butyl-2-oxazolylalkyl sulfide IX (R=Bu-t,R¹═R²═R³═H, Y═NH, Z=NH₂). Coupling of IX with 5-bromo-2-aminothiazole X(R⁴═R⁵═H, L=Br) gives 5-(5-t-butyl-2-oxazolylmethylthio)-2-aminothiazoleXI (R=Bu-t, R═R²═R³═R⁴═R═H). Coupling of XI with N-Boc azacycloalkanoicacid XII (X═OH, R⁶═R⁷═H, m=0, n=2, P=Boc), affords thiazolyl amide XI(R=Bu-t, R¹═R²═R³═R⁴═R⁵═R⁶═R⁶═R⁷═H, m=0, n=2, P=Boc), which afterdeprotection, gives rise to the desired5-(5-t-butyl-2-oxazolylmethylthio)2-azacycloalkanoylaminothiazole I(R=Bu-t, R¹═R²═R³═R⁴═R⁵═R⁶═R⁷═R⁸═H, m=0, n=2), or an analog thereof.

[0071] The present invention further includes two novel key intermediatecompounds of formulae III′ and IX which have been produced from the newprocesses to synthesize5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles of formula I.

[0072] The following examples demonstrate certain aspects of the presentinvention. However, it is to be understood that these examples are forillustration only and do not purport to be wholly definitive as toconditions and scope of this invention. It should be appreciated thatwhen typical reaction conditions (e.g., temperature, reaction times,etc.) have been given, the conditions both above and below the specifiedranges can also be used, though generally less conveniently. Theexamples are conducted at room temperature (about 23° C. to about 28°C.) and at atmospheric pressure. All parts and percents referred toherein are on a weight basis and all temperatures are expressed indegrees centigrade unless otherwise specified.

[0073] A further understanding of the invention may be obtained from thenon-limiting examples which follow below.

EXAMPLE 1

[0074] A. Preparation of α-Azido-pinacolone

[0075] α-Bromo-pinacolone (199.07 g, 1.1115 mol, 1 eq) was combined in1.785 L of acetone with sodium azide (93.9 g, 1.4444 mol, 1.3 eq). Thereaction was stirred at room temperature for 27.5 hours. The resultingslurry was filtered and washed with acetone (3×150 mL). The filtrate wasconcentrated in vacuo to provide 154.3 g (98.4%) of the title compound.HPLC 83.85% at 2.57 minutes (Phenomenex Inc., Torrance, Calif., 5 μm C18column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm).

EXAMPLE 2

[0076] A′ Preparation of α-Hexamethylenetetramino-pinacolone Bromide

[0077] α-Bromo-pinacolone (179 g, 1 mol, 1 eq) was combined in 2 L ofacetone with hexamethylenetetramine (154.21 g, 1.1 mol, 1.1 eq) and thereaction stirred under N₂ at room temperature for 26 hours. Theresulting slurry was filtered, the filter cake was washed with ether(3×50 mL) and dried in vacuo at 50° C. overnight to provide 330 g (100%)of the title compound containing 7% hexamethylenetetramine. HPLCR.T.=0.17 min (Phenomenex Inc., 5 μm C18 column 4.6×50 mm, 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm).

EXAMPLE 3

[0078] B. Preparation of α-Amino-pinacolone Hydrochloride

[0079] α-Azido-pinacolone (128.5 g, 0.911 mol) was combined in 4.2 L ofmethanol with 77.1 mL of concentrated HC1 and 15.42 g of 10% Pd/C. Thereaction mixture was stirred under hydrogen for 1.5 hours. The catalystwas removed by filtration. The solvent was distilled to give a wetsolid. The residual water was azeotropically removed with isopropanol(2×500 mL). Tert-butyl methyl ether (300 mL) was added and the resultingslurry was stirred, filtered, washed with t-butyl methyl ether (3×100mL) and dried to give 131.0 g (95.5%) of the title compound.

EXAMPLE 4

[0080] B′ Preparation of α-Amino-pinacolone Hydrochloride

[0081] α-Hexamethylenetetramino-pinacolone bromide (400 g, 1.254 mol, 1eq) was combined in 2 L of ethanol with 12 N aqueous HCl (439 mL, 5.26mol, 4.2 eq). The reaction was stirred at 75° C. for 1 hour and thenallowed to cool to room temperature, the resulting slurry filtered, thefiltrate concentrated in vacuo and isopropyl alcohol was added. Thesolution was filtered again. Addition of 1.2 L of ether caused thedesired material to precipitate from solution. The material wasfiltered, washed with ether (2×300 mL), and dried in vacuo at 50° C.overnight to provide 184.1 g (97%) of the title compound.

EXAMPLE 5

[0082] C. Preparation of α-N-(2-Chloroacetylamino)-pinacolone

[0083] The title compound of Example 4 (130.96 g, 0.8637 mol, 1 eq) wasdissolved in 3.025 L of CH₂Cl₂ under N₂ at −5° C. Triethylamine (301 mL,2.16 mol, 2.5 eq) was added, followed by chloroacetyl chloride (75.7 mL,0.450 mol, 1.1 eq) in 175 mL of CH₂Cl₂. The resulting slurry was stirredat −5 to −10° C. for 2 hours. Water (1.575 L) was added, followed by 175mL of concentrated HCl. The organic phase was washed a second time with1.75 L of 10% aqueous HCl, and then with 500 mL of water. The organicphase was dried over Na₂SO₄ and concentrated in vacuo to provide 155.26g (93.8%) of the title compound. HPLC R.T.=2.27 min (Phenomenex Inc., 5μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid, 4 mUmin, monitoring at 220 nm).

EXAMPLE 6

[0084] D. Preparation of 5-(t-Butyl)-2-oxazolylmethyl Chloride

[0085] The title compound of Example 5 (180.13 g, 0.9398 mol, 1 eq) wascombined with phosphorus oxychloride (262 mL, 2.8109 mol, 3 eq) underN₂. The reaction was heated at 105° C. for 1 hour, the mixture wascooled to room temperature, and quenched with 1.3 kg of ice. The aqueousphase was extracted with ethyl acetate (1 L, then 2×500 mL). The organicextracts were washed with saturated aqueous NaHCO₃ (4×1 L) which wasback-extracted several times with ethyl acetate. The organic phases werecombined, washed with saturated aqueous NaHCO₃ (500 mL) followed bysaturated aqueous NaCl (300 mL), dried over MgSO₄, and concentrated invacuo to give a brown oil. The crude material was distilled under highvacuum at 100° C. to provide 155.92 g (96%) of the title compound. HPLCR.T.=3.62 min (Phenomenex Inc., 5 μm C18 column 4.6×50 mm, 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm).

[0086] Alternatively, the title compound of Example 5 (10.0 g, 52.17mmol, 1 eq.) in 50 mL of tetrahydrofuran (THF) was combined with(methoxycarbonylsulfamyl)-triethylammonium hydroxide (Burgess' reagent,105.70 mmol, 2.03 eq., generated in situ from 9.2 mL of chlorosulfonylisocyanate, 4.4 mL of methanol and 14.8 mL of triethylamine in 100 mLTHF). The reaction was heated to 45° C. for 1.5 hours. After cooling toroom temperature, the reaction was quenched with water (50 mL). Theorganic layer was separated and washed with saturated NaHCO₃ (2×50 mL)and water (50 mL), dried over MgSO₄ and passed through a small silicagel plug. The solvent was removed to give an oil which was taken up in amixture of 15 mL heptane and 90 mL of t-butyl methyl ether, and thenwashed with 0.2 N HCl (2×25 mL), saturated brine (25 mL) and dried(MgSO₄). Filtration and removal of solvent gave 10.9 g of the titlecompound.

EXAMPLE 7

[0087] E. Preparation of 5-(t-Butyl)-2-oxazolylmethyl ThiouroniumHydrochloride

[0088] The title compound of Example 6 (1.77 g, 10.2 mmol, 1.02 eq) wascombined with thiourea (0.76 g, 9.98 mmol, 1 eq) under N₂ in 10 mL ofabsolute ethanol. The reaction was heated at reflux for 1.5 hours. Themixture was cooled to room temperature and concentrated in vacuo.Trituration of the resulting crude material with t-butyl methyl etherprovided 2.32 g (93%) of the title compound. HPLC R.T.=2.05 min(Phenomenex Inc., 5 μm C18 column 4.6×50 mm, 10-90% aqueous methanolover 4 minutes containing 0.2% phosphoric acid, 4 mLmin, monitoring at220 nm); ¹H NMR (d₆-DMSO): δ9.48 (s, 3H), 6.85 (s, 1H), 4.73 (s, 2H),1.24 (s, 9H).

EXAMPLE 8

[0089] F. Preparation of5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-aminothiazole

[0090] The title compound of Example 7 (1.25 g, 5 mmol, 1 eq) was addedto a mixture of NaOH (3.0 g, 75 mmol, 15 eq), water (10 mL), toluene (10mL) and tetrabutylammonium sulfate (50 mg, 0.086 mmol, 0.017 eq).5-Bromo-2-aminothiazole hydrobromide (1.70 g, 5 mmol, 1 eq) was addedand the reaction was stirred at room temperature for 14.5 hours. Themixture was diluted with water and extracted twice with ethyl acetate,the organic extracts washed with water (4×10 mL), dried over MgSO₄ andconcentrated in vacuo to provide 1.1 g (82%) of the title compound. HPLC86.3% at 2.75 min (Phenomenex Inc., 5 μm C18 column 4.6×50 mm, 10-90%aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm); ¹H NMR (CDCI₃): δ6.97 (s, 1H), 6.59 (s,1H), 5.40 (br s, 2H), 3.89 (s, 2H), 1.27 (s, 9H).

EXAMPLE 9

[0091] G. Preparation of5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-[(N-t-butoxycarbonyl)-azacycloalkanoyl]aminothiazole

[0092] The title compound of Example 8 (9.6 g, 35.6 mmol) was dissolvedin N,N-dimethylformamide (36 mL) and CH₂Cl₂ (100 mL), to which was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.8 g, 72mmol, 2 eq), N-t-butoxycarbonyl-azacycloalkanoic acid (12.6 g, 55 mmol,1.5 eq), and 4-(diemthylamino)pyridine (2 g, 16 mmol, 0.45 eq). Theclear reaction mixture became cloudy as it was stirred at roomtemperature for 3.5 hours. Water (300 mL) and ethyl acetate (200 mL)were added and the resulting precipitate was removed by filtration. Thefiltrate was extracted with ethyl acetate, the organic extracts driedover MgSO₄ and concentrated in vacuo to provide a yellow solid which wascombined with the precipitate obtained by filtration. The solid wasboiled in a mixture of ethanol, acetone and water for 20 minutes,filtered, washed with an ethanol/water mixture and dried to give 16.6 g(97%) of the title compound.

EXAMPLE 10

[0093] H. Preparation of5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-(azacycloalkanoyl)amino-thiazolehydrochloride

[0094] The title compound of Example 9 (16.6 g) was dissolved in 150 mLof CH₂Cl₂, trifluoroacetic acid (30 mL) was added dropwise, and themixture was stirred at room temperature for 2 hours. The reaction wasconcentrated in vacuo, diluted with water (300 mL), cooled in ice, madebasic with sodium hydroxide, and the resulting solid filtered andrecrystallized from ethanol, water and methanol to provide 11.2 g (83%)of the title compound as a yellow solid. The white solid hydrochloridecould be obtained by addition of 18 mL of 1N aqueous HCl to 7 g of thismaterial in methanol. MS: 381 [M+H]⁺; HPLC: 100% at 3.12 min (YMC S5 ODScolumn 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2%phosphoric acid, 4 mL/min, monitoring at 220 nm).

[0095] In the foregoing, there has been provided a detailed descriptionof particular embodiments of the present invention for the purpose ofillustration and not limitation. It is to be understood that all othermodifications, ramifications and equivalents obvious to those havingskill in the art based on this disclosure are intended to be includedwithin the scope of the invention as claimed.

What is claimed is:
 1. A process for the preparation of a compound having the formula I

or a pharmaceutically acceptable salt thereof, wherein: R is alkyl, aryl or heteroaryl; R¹, R², R³, R⁴ and R⁵ are each independently hydrogen, alkyl, aryl or heteroaryl; R⁶ and R⁷ are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; R⁸ is hydrogen, alkyl, aryl, heteroaryl, CONR⁹R¹⁰, COR¹¹ or COOR¹²; R⁹, R¹⁰, R¹¹ and R¹² are each independently hydrogen, alkyl or aryl; m equals 0 to 5; and n equals 0 to 5; which comprises the steps of: (a) reacting an α-substituted ketone having the formula II

wherein: R and R¹ are as described hereinabove; and L is halogen or sulfonate; with a cyclic alkylenetetramine in a suitable solvent or solvent mixture to form a quaternary ammonium salt; (b) reacting the quaternary ammonium salt with an acid in a suitable solvent or solvent mixture to form an α-amino ketone; (c) reacting the α-amino ketone with an α-substituted acyl derivative having the formula V

wherein: R², R³ and L are as described hereinabove; and X is hydroxy, halogen or acyloxy; in the presence of a base in a suitable solvent or solvent mixture to form an amide; or, alternatively, reacting the α-amino ketone with an α-substituted acid in the presence of a coupling reagent to form the corresponding amide; (d) reacting the amide with a dehydrating reagent in a suitable solvent or solvent mixture to give a 2-oxazolylalkyl derivative; (e) reacting the 2-oxazolylalkyl derivative with a sulfur-containing reagent in a suitable solvent or solvent mixture to give a 2-oxazolylalkyl sulfide compound; (f) reacting the 2-oxazolylalkyl sulfide with a 5-halo-2-aminothiazole compound in the presence of a base in a suitable solvent or solvent mixture to give a 5-(2-oxazolylmethylthio)-2-aminothiazole compound; (g) reacting the 5-(2-oxazolylmethylthio)-2-aminothiazole with an azacycloalkanoic acid derivative having the formula XII

wherein: R⁶, R⁷ and X are as described hereinabove; P is a nitrogen-protecting group; m equals 0 to 5; and n equals o to 5; in the presence of a coupling reagent in a suitable solvent or solvent mixture to form a thiazolyl amide; and (h) reacting the thiazolyl amide with a deprotecting reagent in a suitable solvent or solvent mixture to form the compound of formula I.
 2. The process as recited in claim 1, wherein the α-substituted ketone in step (a) is an α-halo ketone.
 3. The process as recited in claim 2, wherein the α-halo ketone is an α-halo aliphatic ketone or an α-halo aromatic ketone.
 4. The process as recited in claim 3, wherein the α-halo ketone is an α-halo pinacolone.
 5. The process as recited in claim 4, wherein the α-halo pinacolone is α-bromo pinacolone.
 6. The process as recited in claim 1, wherein the solvent in step (a) is a hydrocarbon, an ether, an amide, a ketone or a mixture thereof.
 7. The process as recited in claim 6, wherein the solvent is the ketone and the ketone is acetone.
 8. The process as recited in claim 1, wherein the cyclic alkylenetetramine in step (a) is hexamethylenetetramine.
 9. The process as recited in claim 1, wherein the acid in step (b) is HCl, HBr, HI, H₂SO₄ or H₃PO₄.
 10. The process as recited in claim 9, wherein the acid is HCl.
 11. The process as recited in claim 1, wherein the solvent in step (b) is a hydrocarbon, an ether, an alcohol or a mixture thereof.
 12. The process as recited in claim 11, wherein the solvent is the alcohol and the alcohol is ethanol.
 13. The process as recited in claim 1, further comprising isolating the α-amino ketone product as the salt or free base form before performing step (c).
 14. The process as recited in claim 1, wherein the α-substituted acyl derivative in step (c) is an α-halo acyl halide.
 15. The process as recited in claim 14, wherein the α-halo acyl halide is α-chloroacetyl chloride.
 16. The process as recited in claim 1, wherein the base in step (c) is an aromatic organic amine or an aliphatic organic amine.
 17. The process as recited in claim 16, wherein the base is the aliphatic organic amine and the aliphatic organic amine is triethylamine.
 18. The process as recited in claim 1, wherein the α-substituted acid in step (c) is an α-halo acid halide and the coupling reagent is water-soluble.
 19. The process as recited in claim 18, wherein the coupling reagent is a carbodiimide, a haloformate or a thionyl halide.
 20. The process as recited in claim 1, wherein the dehydrating reagent in step (d) is an acid, an acid anhydride or a base.
 21. The process as recited in claim 1, wherein the dehydrating reagent in step (d) is concentrated sulfuric acid, polyphosphoric acid, trichlorophosphorus oxide, tribromophosphorus oxide or (methoxycarbonylsulfamoyl)triethylammonium hydroxide.
 22. The process as recited in claim 21, wherein the dehydrating reagent is (methoxycarbonylsulfamoyl)triethylammonium hydroxide.
 23. The process as recited in claim 1, wherein the solvent in step (d) is tetrahydrofuran.
 24. The process as recited in claim 1, wherein the dehydrating reagent in step (d) is (methoxycarbonylsulfamoyl)triethylammonium hydroxide and the solvent is tetrahydrofuran.
 25. The process as recited in claim 1, wherein the sulfur-containing reagent in step (e) is an N-substituted thiourea, an unsubstituted thiourea, a thio acid or a salt thereof, or a xanthic acid or a salt thereof.
 26. The process as recited in claim 25, wherein the sulfur-containing reagent is thiourea, thioacetic acid or the salt thereof, or ethylxanthic acid potassium salt.
 27. The process as recited in claim 1, wherein the 5-halo-2-aminothiazole compound in step (f) is 5-bromo-2-aminothiazole.
 28. The process as recited in claim 1, wherein the base in step (f) is a metal hydroxide, a metal alkoxide, a metal carbonate or an aqueous amine.
 29. The process as recited in claim 28, wherein the base is the metal hydroxide and the metal hydroxide is sodium hydroxide.
 30. The process as recited in claim 1, wherein the solvent in step (f) is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester, an amide, an alcohol or a mixture thereof.
 31. The process as recited in claim 30, wherein the solvent is the halogenated hydrocarbon and the halogenated hydrocarbon is dichloromethane.
 32. The process as recited in claim 1, wherein the nitrogen-protecting group in step (g) is Boc or Cbz.
 33. The process as recited in claim 1, wherein the coupling reagent in step (g) is a carbodiimide, a haloformate or a thionyl halide.
 34. The process as recited in claim 33, wherein the coupling reagent is the carbodiimide and the carbodiimide is an alkylcarbodiimide.
 35. A process for the preparation of a compound having the formula III′

or a salt thereof, wherein: R is alkyl; R¹ is hydrogen, alkyl, aryl or heteroaryl; and L is halogen or a sulfonate; which comprises reacting an α-substituted ketone having the formula II

wherein: R, R¹ and L are as described hereinabove; with a cyclic alkylenetetramine in a suitable solvent or solvent mixture to form the compound of formula III′.
 36. The process as recited in claim 35, wherein R is t-butyl.
 37. The process as recited in claim 35, wherein the cyclic alkylenetetramine is hexamethylenetetramine.
 38. A process for the preparation of a compound having the formula IX

or a salt thereof, wherein: R is alky, aryl or heteroaryl; R¹, R² and R³ are each independently hydrogen, alkyl, aryl or heteroaryl; Y is O, S, NH, N-alkyl, N-aryl or N-acyl; and Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH₂, N-alkyl, N-aryl or N-acyl; which comprises reacting a 2-oxazolylalkyl derivative having the formula VII

wherein: R, R¹, R² and R³ are as described hereinabove; and p1 L is halogen or sulfonate; with a sulfur-containing reagent in a suitable solvent or a solvent mixture to form the compound of formula IX.
 39. The process as recited in claim 38, wherein the sulfur-containing reagent is an N-substituted thiourea, an unsubstituted thiourea, a thio acid or a salt thereof, or a xanthic acid or a salt thereof.
 40. The process as recited in claim 39, wherein the sulfur-containing reagent is thiourea, thioacetic acid or the salt thereof, or ethylxanthic acid potassium salt.
 41. The process as recited in claim 38, wherein the solvent is a hydrocarbon, a halogenated hydrocarbon, an ether, an ester, an amide, an alcohol or a mixture thereof.
 42. The process as recited in claim 41, wherein the solvent is the alcohol and the alcohol is methanol or ethanol.
 43. A compound having the formula III′

or a salt thereof, wherein: R is alkyl; R¹ is hydrogen, alkyl, aryl or heteroaryl; and L is halogen or a sulfonate.
 44. The compound as recited in claim 43, wherein R is t-butyl.
 45. The compound as recited in claim 44, wherein R¹ is hydrogen.
 46. The compound as recited in claim 45, wherein L is halogen.
 47. The compound as recited in claim 46, α-hexamethylenetetramino-pinacolone bromide.
 48. A compound having the formula IX

or a salt thereof, wherein: R is alkyl, aryl or heteroaryl; R¹, R² and R³ are each independently hydrogen, alkyl, aryl or heteroaryl; Y is O, S, NH, N-alkyl, N-aryl or N-acyl; and Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH₂, N-alkyl, N-aryl or N-acyl.
 49. The compound as recited in claim 48, wherein R is t-butyl; Y is NH, N-alkyl, N-aryl or N-acyl and Z is NH₂, N-alkyl, N-aryl or N-acyl.
 50. The compound as recited in claim 49, wherein the salt is hydrochloride.
 51. The compound as recited in claim 50, 5-(t-butyl)-2-oxazolylmethyl thiouronium hydrochloride. 